N, n-disubstituted 9-xanthenecarboxamides



Patented Dec. 1, 1953 N,N-DISUBSTITUTED Q-XANTHEN'E CAR- BOXAMIDES John W. Cusic, Skokie, 111., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application August 2, 1951, Serial N0. 240,060

11 Claims. 1 The present invention relates to a new class of heterocyclic organic compounds and in particular to the N,N-disubstituted Q-Xanthenecarboxamides. These compounds can be represented by the structural formula In this formula R is a hydrocarbon radical of no more than 15 carbon atoms and R is a lower alkyl radical or a basically substituted lower alkyl radical.

Among the radicals which R can represent are such lower alkyl radicals as methyl, ethyl, propyl, butyl, amyl, and hexyl. But of particular interest are those hydrocarbon radicals which con tain a carbocyclic ring and especially a benzene ring such as phenyl, benzyl, phenylethyl, and lower nuclear alkyl substitution products thereof, such as tolyl, xylyl, cumyl, cymyl, and the like.

Also of special value have been found the compounds wherein the above mentioned benzene ring is partially or totally hydrogenated as in the case of cyclohexenyl, tetrahydrophenylalkyl and related hydrocarbons, and other cycloalkyl rings as cyclopentyl.

The radical R in the above formula can be a lower alkyl radical as defined above. However, of special interest are the basically substituted alkyl radicals of the type salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide; phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The compounds which constitute this invention are valuable intermediates in organic synthesis. These compounds, and in particular the basically substituted allcyl derivatives, have been found to possess a number of highly useful pharmacodynamic properties. They have a pronounced effect on the circulatory system and the kidney. The salts and especially the quaternary salts, are of value because of their inhibitory effect on certain autonomic nervous functions. These salts are useful in-combatting parasites.

My invention will be described more fully in conjunction with the following examples. It should be understood, however, that these examples are given by Way of illustration only and that the invention is not to 'be'construed as limited in spirit or in scope by the details set forth. It will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention. In each of these examples tem peratures are given uncorrected in degrees centigrade (C.) and quantities of materials in parts by weight.

EXAMPLE 1 N ,N-diethyl-Q-aanthenecaTbOxamide A mixture of 244 parts of 9-xanthenecarboxylic acid chloride is treated with parts of diethylamine and 1500 parts of benzene at reflux temperature for 2 hours. After cooling the mixture is treated with dilute hydrochloric acid solution and the benzene layer is separated, dried over anhydrous calcium chloride, stirred with charcoal and evaporated. The N,N-diethyl-Q-XanthenecarboXamide thus obtained is recrystallized from ethanol. The colorless crystals have the structural formula 2,66 1,358 3 4 EXAMPLE 2 EXAMPLE 5 N fi-dieth'ylaminoethyl) -9-a:anthene- N (a-piperz'dinobutyl) -N- (ii-3,4-dimethylphencarboxanilide ylethyl) -9-xanthenecarboxamide A mixture of 244 parts of 9-xanthenecarboxylic acid chloride and 192 IiEIi1-tS fiN- (fl-Tdl ethylaminothyl)-aniline in 1600 parts of benzene is heated at reflux temperature for 2 hours. After cooling the solid precipitate is collected tin a filter, decolorized with the aid of charcoal and recrystallized from dilute iso'p'ropanol. The' hydrochloride of N-(pl-diethylaminoethyl)-9-xanthenecarboxanilide thus obtained meltsiat about 229-230 C. It has the structural' formula h ncn -cnemcimh "H, Cl

244 parts of 9-xanthenecarb0xylic Iacid chlo ride, 220 parts of -1-(fl benzylaminoethyl)morpholine and leooparts of "biitanone are stirred. There is an immediate reaction '--with 'iormation of a precipitate. The-mixture is heatedat reflux temperature for 2 hours and then :chilled. The resulting precipitate is collected on 'a efilter ;and recrystallized from dilute isopropanol. --The hydrochloride of sN-benzyl-N-(B-morpholinoethyl) -9-xanthenecarboxamide thus obtained melts at about -21-6.217-C. It hasthestructural 'formula aHa H01 A mixture of 156 parts of l-(a-aminobutyD- rpip'eridine and 3169 parts of 4-(B c'hloroethyD- xylene in 1200 parts of toluene' is heated at reflux temperature for 10 hours. The reaction .product is poured over ice and treated with dilute hydrochloric acid. The aqueous layer is rendered alkaline by addition of sodium hydroxide and then extracted with ether. The ether extract is idr iedmver anhydrous sodium sulfate, filtered and =evaporated. 2'88'3parts of N-(B-piperidinobutyD- 3,4-dimethylphenethylamine thus obtained are lboiled "with 24.4 parts of 9-xanthenecarboxylic aacid chloride and 2000 parts of benzene at reflux temperature for 3 hours. After cooling the mixture istreated with dilute hydrochloric acid. The acidic layer is separated, shaken with ether, and then rendered alkaline 'with dilute sodium Ihy- "d'roxidezan'd extracted with'ether. 'Theether extract .is dried over anhydrous potassium carbonate, stirred with decolorizing charcoal, filtered and evaporated. The resulting oil consists 0f N (t-piperidinobutyl) -N- (5-3.4-dimethylphenylethyl) -9-xanthenec'arboxamide which has the structural formula shown below. A white crystalline hydrochloride ;is obtained by treatment with alcoholic hydrogenschloride. This salt has the structural formula on "om-om -o o-1 I-o Hz-CHr-OHPCHfl-ITI )CH:

en, oer-on,

.A :mixture :of 372 .parts [of :2-methyl-1;2",3,6- itetrahydrobenzaldehyde and 1400 :parts of fl-Tdi- =iethylaniino +2-aminoethanezis ihydrogenated with 40 parts of Raney nickel, .110 .parts of a 111% Lcliloroplatinic acid solution and 1200 parts of ethanol at 50 to 20 lbs. pressure. After opening of the bomb the contents are filtered and most of the solvent is removed from the filtrate by evaporation. The concentrate .is treated with ice and dilute hydrochloricacid. The aqueous layer is separated and rendered alkaline by addition of dilute sodium hydroxide and extracted with ether. The ether extract-fis dried over anhydrous potassium carlzaonate, :filtered and evaporated. The *N tfi-diethyiaminoethyl) 2emethyl 1j23l6- :tetrahydrobenzylamine is distilled :at about 86 0. at 2 1mm. pressure.

228aparts" of the fdistillate are-'treated with 244 '70 parts 'of rQ-xanthene'carbQXyIic racid .chloride in 2400 partsaofwbutanone-and heatedlat refinxrtemperature for 24 ihours. The rmixture :is 'ztlren :stirred with charcoal, filtered awhile lhot, and cooled. "The precipitated:hydrochlorideiof[N413- 3 5 diethylaminoethyl) -1N- (2emethyl41,2,3;6 tetrahydroxide and extracted with ether.

drobenzyl)-9-xanthenecarboxamide melts at about 188-189 C. It has the structural formula ONCHr-CHz-N I OH: I 02115 H in CH: OHCHa H Ha EXANIPLE 7 N cycZohexyZ-N-(p diethylaminoethyl) -9-s:an-

thenecarboacamide A mixture of 393 parts of cyclohexanone, 464 parts of 1-diethylamino-2-aminoethane, 240 parts of ethanol and 40 parts of Raney nickel is hydrogenated in a Parr bomb at 120 C. and 500 lbs. pressure for 20 hours. The contents are removed and the filtrate treated with dilute hydrochloric acid. The acidic solution is rendered yl)-9-xanthenecarboxamide hydrochloride is recrystallized from isopropanol. It melts at about 216-217 C. The base has the structural formula v H C \C H8 EXANIPLE 8 N -(3 methylcyclopentyl) -N-(v-dimethylaminobutyl) -9-:x:anthenecarboa:amide To a mixture of 196 parts of B-methylcyclopentanone and 232 parts of N,N-dimethylputrescine, 94 parts of 98% formic acid are gradually added. The initial reaction is controlled by efiicient refrigeration. The mixture is then heated at reflux temperature for 6 hours with agitation and permitted to stand at room temperature for several hours. After cooling 220 parts of concentrated hydrochloric acid are added and refluxing is resumed for 7 hours. 300 parts of water are added and the mixture is washed with benzene, made alkaline with potassium carbonate and extracted with benzene. The benzene extract is washed with water, dried with anhydrous sodium sulfate and evaporated in vacuo. 198 parts of the resulting N,N-dimethyl- A precipitate begins to occur within a N-(3-methylcyclopentyl)putrescine are heated at reflux temperature with 244 parts of 9-xanthenecarboxylic acid chloride in 2600 parts of benzene with mechanical stirring for 5 to 6 hours and then permitted to cool. The resulting white crystals are dissolved in water and the solution is rendered alkaline by addition of dilute potassium hydroxide. The base is extracted with ether and the ether extract dried over anhydrous potassium carbonate, filtered and evaporated. The resulting base has the structural formula I claim: 1. The 9-xanthenecarboxamides of the structural formula wherein R. is a hydrogenated lower phenylalkyl radical of no more than 10 carbon atoms, A is a lower alkylene radical containing at least 2 carbon atoms and R. and R are lower alkyl radicals.

2. The xanthene-9-carboxamides of the structural formula wherein R. is a lower-alkyl substituted lower tetrahydrophenylalkyl radical of no more than 10 carbon atoms, A 15a lower alkylene radical containing at least 2 carbon atoms, and R and R" are lower alkyl radicals.

3. The xanthene-Q-carboxamides of the structural formula 5 on, CH-CHB H H: CH

wherein A is a lower alkylene radical containing at least 2 carbon atoms and R, and R." are lower alkyl radicals.

4.. The. xanthenesil -carboxaniicles oi the structural formula wherein R is a lower monocyclic hydrocarbon radical of no more than 10 carbon atoms and containing to 6 carbon atoms in the monocycle, A is a lower alkylene radical containing at least 2 carbon atoms and Rf and R are lower alkyl radicals.

5. The xanthene-Q-carboxamides. of the structural' formula wherein R is a phenylalkyl radical of no more than 10 carbon atoms, A is a lower alkylene radical containing at least 2 carbon atoms, and R and R are lower alkyl radicals.

6. The xanthene-Q-carboxamides of the structural formula wherein A is a lower alkylene radical containing at least two carbon atoms and R. and R" are lower alkyl radicals.

'7. The xanthene-Q-carboxamides of the structural formula 8 wherein R is a lower cycloalkyl radical. containing 5. to 6' nuclear carbon atoms, A is a. lower alkylene radical containing at least 2 carbon atoms and R and R" are lower alkyl radicals.

8. The xanthene-Q-carboxamides of the structural formula wherein R'is apheny l. radical,,A is'a lower'alkylene radical containing. at least. 2.. carbon atoms,

and Bi andR," are. lower alkyl radicals.

JOHN W. CIJSIC;

No references cited.

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8. THE XANTHENE-9-CARBOXAMIDES OF THE STRUCTURAL FORMULA 